Animesh Pardanani1, Claire Harrison2, Jorge E Cortes3, Francisco Cervantes4, Ruben A Mesa5, Donald Milligan6, Tamás Masszi7, Elena Mishchenko8, Eric Jourdan9, Alessandro M Vannucchi10, Mark W Drummond11, Mindaugas Jurgutis12, Kazimierz Kuliczkowski13, Emanuil Gheorghita14, Francesco Passamonti15, Frank Neumann16, Abhay Patki16, Guozhi Gao16, Ayalew Tefferi1. 1. Department of Medicine, Mayo Clinic, Rochester, Minnesota. 2. Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, England. 3. University of Texas MD Anderson Cancer Center, Houston. 4. Hospital Clinic, IDIBAPS University of Barcelona, Barcelona, Spain. 5. Division of Hematology-Oncology, Mayo Clinic, Scottsdale, Arizona. 6. Centre for Haematology and Stem Cell Transplantation, Heartlands Hospital, Birmingham, England. 7. Department of Haematology and Stem Cell Transplantation, St István and St László Hospital, Budapest, Hungary. 8. Hematology-Oncology Unit, Bnai-Zion Medical Center, Haifa, Israel. 9. Groupe Hospitalo-Universitaire Nimes, Nimes, France. 10. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. 11. Beatson West of Scotland Cancer Centre, Gartnavel General Hospital, Glasgow, Scotland. 12. Hematology Department, Klaipeda Seamen's Hospital, Klaipeda, Lithuania. 13. Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland. 14. Brasov Country Hospital, Brasov, Romania. 15. University Hospital Ospedale di Circolo e Fondazione Macchi, Varese, Italy. 16. Sanofi Oncology, Cambridge, Massachusetts.
Abstract
IMPORTANCE: Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials. OBJECTIVE: To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled phase 3 study in 94 sites in 24 countries in which 289 adult patients (≥18 years of age) with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF were randomly assigned between December 2011 and September 2012 to once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles. MAIN OUTCOMES AND MEASURES: The primary end point was spleen response (≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed 4 weeks later. The main secondary end point was symptom response (≥50% reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form). RESULTS: The primary end point was achieved by 35 of 96 (36% [95% CI, 27%-46%]) and 39 of 97 (40% [95% CI, 30%-50%]) patients in the fedratinib 400-mg and 500-mg groups, vs 1 of 96 (1% [95% CI, 0%-3%]) in the placebo group (P < .001). Symptom response rates at week 24 were 33 of 91 (36% [95% CI, 26%-46%]), 31 of 91 (34% [95% CI, 24%-44%]), and 6 of 85 (7% [95% CI, 2%-13%]) in the fedratinib 400-mg, 500-mg, and placebo groups, respectively (P < .001). Common adverse events with fedratinib treatment were anemia, gastrointestinal symptoms, and increased levels of liver transaminases, serum creatinine, and pancreatic enzymes. Encephalopathy was reported in 4 women who received fedratinib 500 mg/d. A diagnosis of Wernicke encephalopathy was supported by magnetic resonance imaging in 3 cases and suspected clinically in 1 case. CONCLUSIONS AND RELEVANCE: Fedratinib therapy significantly reduced splenomegaly and symptom burden in patients with MF. These benefits were accompanied by toxic effects in some patients, the most important being encephalopathy of unknown mechanism. Clinical development of fedratinib was subsequently discontinued. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01437787.
IMPORTANCE: Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials. OBJECTIVE: To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled phase 3 study in 94 sites in 24 countries in which 289 adult patients (≥18 years of age) with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF were randomly assigned between December 2011 and September 2012 to once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles. MAIN OUTCOMES AND MEASURES: The primary end point was spleen response (≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed 4 weeks later. The main secondary end point was symptom response (≥50% reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form). RESULTS: The primary end point was achieved by 35 of 96 (36% [95% CI, 27%-46%]) and 39 of 97 (40% [95% CI, 30%-50%]) patients in the fedratinib 400-mg and 500-mg groups, vs 1 of 96 (1% [95% CI, 0%-3%]) in the placebo group (P < .001). Symptom response rates at week 24 were 33 of 91 (36% [95% CI, 26%-46%]), 31 of 91 (34% [95% CI, 24%-44%]), and 6 of 85 (7% [95% CI, 2%-13%]) in the fedratinib 400-mg, 500-mg, and placebo groups, respectively (P < .001). Common adverse events with fedratinib treatment were anemia, gastrointestinal symptoms, and increased levels of liver transaminases, serum creatinine, and pancreatic enzymes. Encephalopathy was reported in 4 women who received fedratinib 500 mg/d. A diagnosis of Wernicke encephalopathy was supported by magnetic resonance imaging in 3 cases and suspected clinically in 1 case. CONCLUSIONS AND RELEVANCE: Fedratinib therapy significantly reduced splenomegaly and symptom burden in patients with MF. These benefits were accompanied by toxic effects in some patients, the most important being encephalopathy of unknown mechanism. Clinical development of fedratinib was subsequently discontinued. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01437787.
Authors: Vikas Gupta; Ruben A Mesa; Michael W N Deininger; Candido E Rivera; Shireen Sirhan; Carrie Baker Brachmann; Helen Collins; Jun Kawashima; Yan Xin; Srdan Verstovsek Journal: Haematologica Date: 2016-09-15 Impact factor: 9.941
Authors: Dongqing Yan; Anthony D Pomicter; Srinivas Tantravahi; Clinton C Mason; Anna V Senina; Jonathan M Ahmann; Qiang Wang; Hein Than; Ami B Patel; William L Heaton; Anna M Eiring; Phillip M Clair; Kevin C Gantz; Hannah M Redwine; Sabina I Swierczek; Brayden J Halverson; Erkan Baloglu; Sharon Shacham; Jamshid S Khorashad; Todd W Kelley; Mohamed E Salama; Rodney R Miles; Kenneth M Boucher; Josef T Prchal; Thomas O'Hare; Michael W Deininger Journal: Clin Cancer Res Date: 2018-12-18 Impact factor: 12.531
Authors: Shane A Curran; Justin A Shyer; Erin T St Angelo; Lillian R Talbot; Sneh Sharma; David J Chung; Glenn Heller; Katharine C Hsu; Brian C Betts; James W Young Journal: Cancer Immunol Res Date: 2016-12-06 Impact factor: 11.151